This invention relates to benzocycloheptenes of general formula I 
in which
R1 and R2, independently of one another, stand for a hydrogen atom, a hydroxy group, an optionally substituted C1-C10 alkoxy group, an optionally substituted C1-C10 alkanoyloxy group or an optionally substituted C7-C15 aroyloxy group, and
Y stands for a side chain xe2x80x94Axe2x80x94Bxe2x80x94Z,
whereby
A means a direct bond or an oxygen atom,
B means a straight-chain or branched-chain, optionally substituted alkylene, alkenylene or alkinylene group with up to 10 carbon atoms,
Z means a group xe2x80x94Dxe2x80x94SOxxe2x80x94Exe2x80x94G, an amino group xe2x80x94NR7R8 or a substituent G, in which
D means a direct bond or a group xe2x80x94NR3(R4xe2x80x94), R3 means a straight-chain or branched-chain alkyl, alkenyl or alkinyl group with up to 10 carbon atoms and R4 means a straight-chain or branched-chain, optionally substituted alkylene, alkenylene or alkinylene group with up to 10 carbon atoms, whereby the nitrogen atom also can be incorporated in a 4- to 7-membered ring system,
the nitrogen atom can also be incorporated into a 4- to 7-membered ring system,
x means 0, 1 or 2,
E means a straight-chain or branched-chain, optionally substituted alkylene, alkenylene or alkinylene group with up to 10 carbon atoms,
G means a partially or completely fluorinated, straight-chain or branched-chain alkyl group with up to 5 carbon atoms, an optionally substituted aryl or heteroaryl radical, a carbamoyl radical xe2x80x94C(O)xe2x80x94NR5R6 with R5 and R6 in the meaning of R7 and R8, a halogen atom or a hydrogen atom,
R7 and R8, independently of one another, mean a hydrogen atom, a straight-chain or branched-chain, optionally partially fluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which can be interrupted by one to three heteroatoms xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94 and groupings xe2x80x94NR9xe2x80x94, in which R9 means a hydrogen atom or a C1-C3 alkyl radical, an aryl or heteroaryl radical that is optionally substituted in one or two places, a C3-C10 cycloalkyl radical that is optionally substituted in one or two places, a C4-C15 cycloalkylalkyl radical that is optionally substituted in one or two places, a C7-C20 aralkyl radical that is optionally substituted in one or two places, a heteroaryl-C1-C8 alkyl radical that is optionally substituted in one or two places or an optionally substituted aminoalkyl radical, a biphenylene radical or a radical of formula xe2x80x94C(O)R10, in which R10 can have the meanings that are indicated above for R7 or R8,
R7 and R8 with the nitrogen atom, to which they are bonded, form a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted, and in xe2x80x94Axe2x80x94Bxe2x80x94Z, if A stands for an oxygen atom and Z stands for G, G cannot be a hydrogen atom or a halogen atom, or if A stands for an oxygen atom and Z stands for an amino group xe2x80x94NR7R8, in which R7 and R8 in each case mean a methyl group or together with the nitrogen atom form a pyrrolidine ring, B has at least 3 carbon atoms.
As a C1-C10 alkoxy group R1 or R2, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, heptyloxy, hexyloxy or decyloxy group is suitable.
The alkanoyl groups that are contained in R1 and R2 of general formula I are to contain 1 to 20 carbon atoms in each case, whereby formyl, acetyl, propionyl and isopropionyl groups are preferred.
Aroyl radicals R1 or R2 are primarily benzoates and benzoates that are substituted in the phenyl radical; they can also be the other aroyl and heteroaroyl radicals that are derived from the aryl radicals that are explained in more detail below.
For B, primarily a straight-chain alkylene group with 1 to 6 carbon atoms is suitable.
As alkyl groups R3, R7 and R8, straight-chain or branched-chain alkyl groups with up to 10 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
The latter can have up to 3 unsaturations (double bonds and/or triple bonds).
Alkyl groups R3, R7 and R8 can be partially or completely fluorinated or substituted.
As a partially or completely fluorinated straight-chain or branched C1-C10 alkyl group, for example, the trifluoromethyl group, pentafluoroethyl group, 2,2,2-trifluoroethyl group, 4,4,4-trifluorobutyl group, 3,3,4,4,4-pentafluorobutyl group, 4,4,5,5,5-pentafluoropentyl group or nonafluorobutyl group can be mentioned.
The latter can also have up to 3 unsaturations (double bonds and/or triple bonds).
The C1-C3 alkyl radical that stands for R9 is a methyl, ethyl, propyl or isopropyl radical; the methyl radical is preferred.
For aryl radical R3 or R4 and G and the aryl radical within arylalkyl radical R3 or R4, the following radicals that are optionally substituted in one or more places can stand for:
a monocyclic, carbocyclic radical, for example the phenyl radical;
a monocyclic, heterocyclic radical, for example the thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, specifically all possible isomers relative to the positions of the heteroatoms as well as the interface sites to the sulfur atom in the side chain;
a condensed carbocyclic radical, for example the naphthyl or phenanthrenyl radical;
a condensed radical, which consists of carbocyclic and heterocyclic radicals, for example the benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, xcex2-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or a condensed polyheterocyclic system, for example furo[2,3-b]pyrrole or thieno[2,3-b]furan.
As substituents to radicals B, G, R3, R4, R5, R6, R7, R8 and R10 as well as R3 together with R4, the substituents below are suitable, whereby the radicals can be substituted in one or more places, identically or differently, with these substituents:
Halogen atoms: fluorine, chlorine, bromine, iodine;
amino-, mono(C1-8 alkyl)- or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, especially methylamino or ethylamino, dimethylamino, diethylamino or methylethylamino; di(aralkyl)amino, whereby both aralkyl groups are identical or different;
hydroxyl groups;
free, esterified carboxyl groups or carboxyl groups that are present in the form of a salt: esterified with a carboxycarbonyl group, for example methoxycarbonyl or ethoxycarbonyl; as salt, for example in the form of sodium or potassium salt;
alkyl groups with 1 to 8 carbon atoms, such as, for example, the methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl group, optionally substituted with one or more halogen atoms, for example with fluorine, such as the trifluoromethyl or pentafluoroethyl group;
oxo, azido, cyano, nitro or formyl groups;
acyl groups such as acetyl, propionyl, butyryl, benzoyl;
acyloxy groups such as acetoxy, radicals of formula xe2x80x94Oxe2x80x94COxe2x80x94(CH2)nxe2x80x94COOH with n=1 to 5;
C1-C4 alkoxy groups, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy;
alkylthio groups, for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, all optionally fluorinated,
carbamoyl groups;
alkenyl groups, for example vinyl, propenyl;
alkinyl groups, for example ethinyl, propinyl;
C6-C12 aryl groups, such as phenyl, furyl, thienyl, which in turn can be substituted in one to three places.
As a cycloalkyl group for substituents R7 and R8, substituted and unsubstituted radicals with 3 to 10 carbon atoms are suitable; mainly the cyclopropyl and cyclopentyl groups and, as an alkylcyclolalkyl group, the methylcyclopropyl and methylcyclopentyl groups can be mentioned.
The C7-C20 aralkyl radicals in R7 and R8 can contain up to 14 C atoms, preferably 6 to 10 C atoms, in the ring, and 1 to 8, preferably 1 to 4 C atoms in the alkyl chain.
As a heteroaryl part, a heteroaryl-C1-C8 alkyl radical in R7 and R8 has one of the already mentioned heteroaryl radicals; the alkyl chain comes with 1 to 8, preferably 1 to 4 C-atoms.
As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, and napthylethyl are suitable, and as heteroaryl-alkyl radicals, furylmethyl, thienylethyl and pyridylpropyl are suitable.
The rings can be substituted in one or more places.
If R7 and R8 with the nitrogen atom, to which they are bonded, contain a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, this is especially a pyrrolidine, piperidine, morpholine or piperazine ring.
As substituents for aryl, heteroaryl, aralkyl and heteroarylalkyl radicals, there can be mentioned especially a trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(C1-8 alkyl) or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, or the 1-methoxyacetylamino radical.
The sulfur atom in the side chain can be present as a single sulfur bridge (sulfide), as a sulfone or sulfoxide.
Free hydroxy groups in the compounds of general formula I can be modified functionally, for example by etherification or esterification; free hydroxy groups are preferred, however.
As ether and acyl radicals (protective groups), the radicals that are known to one skilled in the art, such as, e.g., the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, methyl, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, butyryl, pivalyl, benzoyl radicals are suitable. A survey is found in, e.g., xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Theodora W. Green, John Wiley and Sons).
As specific side chains, in which A stands for an oxygen atom, there can be mentioned
xe2x80x94Oxe2x80x94(CH2)5S(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)5SO2(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94SOxe2x80x94(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)5S(CH2)xe2x80x94C(O)N(CH3)xe2x80x94(CH2)3CH3 
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)xe2x80x94C(O)N(CH3)xe2x80x94(CH2)3CH3 
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94NH(CH2)OH
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)2xe2x80x94SO(CH2)xe2x80x94C(O)N(CH3)xe2x80x94(CH2)3CH3 
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)2xe2x80x94SO2(CH2)xe2x80x94C(O)N(CH3)xe2x80x94(CH2)3CH3 
xe2x80x94Oxe2x80x94(CH2)6S(CH2)xe2x80x94C(O)N(CH3)xe2x80x94(CH2)3CH3 
xe2x80x94Oxe2x80x94(CH2)6SO(CH2)xe2x80x94C(O)N(CH3)xe2x80x94(CH2)3CH3 
xe2x80x94Oxe2x80x94CH3 
xe2x80x94Oxe2x80x94(CH2)5xe2x80x94F
xe2x80x94Oxe2x80x94(CH2)4xe2x80x94F
xe2x80x94Oxe2x80x94(CH2)3xe2x80x94F
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94F
xe2x80x94Oxe2x80x94(CH2)5xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)4xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)3xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Cl
xe2x80x94Oxe2x80x94(CH2)6S(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)6SO(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)6SO(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)2C3F7 
xe2x80x94Oxe2x80x94(CH2)2-1-Pyrrolidinyl
xe2x80x94Oxe2x80x94(CH2)4S(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)4SO(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)4SO2(CH2)3C2F5 
xe2x80x94Oxe2x80x94(CH2)4S(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)4SO(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)6S(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)6SO(CH2)-2-Pyridyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)-2-Furyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-2-Furyl
xe2x80x94Oxe2x80x94(CH2)5SO2(CH2)-2-Furyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)-2-Thienyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-2-Thienyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)4xe2x80x94F
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)4xe2x80x94F
xe2x80x94Oxe2x80x94(CH2)5S(CH2)3xe2x80x94CF3 
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)3xe2x80x94CF3 
xe2x80x94Oxe2x80x94(CH2)5xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94C2F5 
xe2x80x94Oxe2x80x94(CH2)5S(CH2)-Phenyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-2-Phenyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)-p-Tolyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-p-Tolyl
xe2x80x94Oxe2x80x94(CH2)5S(CH2)-p-CF3-Phenyl
xe2x80x94Oxe2x80x94(CH2)5SO(CH2)-p-CF3-Phenyl
xe2x80x94Oxe2x80x94(CH2)5S-Phenyl
xe2x80x94Oxe2x80x94(CH2)5SO-Phenyl
xe2x80x94Oxe2x80x94(CH2)5Sxe2x80x94(p-Tolyl)
xe2x80x94Oxe2x80x94(CH2)5SOxe2x80x94(p-Tolyl)
xe2x80x94Oxe2x80x94(CH2)5Sxe2x80x94(p-CF3-Phenyl)
xe2x80x94Oxe2x80x94(CH2)5SOxe2x80x94(p-CF3-Phenyl)
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)2 
As side chains, in which A stands for a direct bond, for example, the following are suitable (DE 1 98 06 357.1)
xe2x80x94(CH2)5N(CH3)(CH2)3C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)2C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)3C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)3C8F17 
xe2x80x94(CH2)5N(CH3)(CH2)6C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)6C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)6C8F17 
xe2x80x94(CH2)5N(CH3)H
xe2x80x94(CH2)5N(CH3)(CH2)9H
xe2x80x94(CH2)5-1-Pyrrolidinyl
xe2x80x94(CH2)9S(CH2)3C2F5 
xe2x80x94(CH2)9SO(CH2)3C2F5 
xe2x80x94(CH2)9SO2(CH2)3C2F5.
In addition, the side chains of general partial formula 
are suitable whereby
a is 4, 5 or 6,
b is 0, 1 or 2,
c is 0, 1 or 2,
R5 is a hydrogen atom or a C1-5 alkyl group,
R6 and R7 are each a hydrogen atom, or
R5 and R6 together are an alkylene group xe2x80x94(CH2)dxe2x80x94 with d=2, 3, 4 or 5, and R7 is a hydrogen atom or
R5 and R7 together are an alkylene group xe2x80x94(CH2)exe2x80x94 with e=2, 3 or 4 and R6 is a hydrogen atom, and
U is an unsubstituted ethyl radical or an ethyl radical that is fluorinated in one to five places, or
the terminal substituent xe2x80x94(CH2)3xe2x80x94U in the side chain is replaced by an optionally substituted aryl or heteroaryl radical, which is bonded directly or via a mono-, di- or trimethylene group to the sulfur atom, and of the latter in turn especially the side chains
xe2x80x94(CH2)5N(CH3)(CH2)3S(CH2)3C2F5 and
xe2x80x94(CH2)5N(R5)(CHR6)CH2S(CH2)3C2F5 with R5+R6=xe2x80x94(CH2)3xe2x80x94.
For the purposes of this invention, the preferred compounds are
(4,4,5,5,5-Pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfide
(4,4,5,5,5-pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfoxide
methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine
methyl-[3-(4,4,5,5,5-pentafluoropentylsulfinyl)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine
S-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetate
N-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide
N-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy)-pentanesulfinyl}-acetamide
5-{4-[5-(4,4,5,5,5-pentafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
N-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide
5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
N-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide
N-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamide
N-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamide
6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
N-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexanesulfinyl}-N-methyl-acetamide
N-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamide
6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentane-sulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[4-(4,4,5,5,5-pentafluoro-pentylthio)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[6-(pyridin-2-ylmethylthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[4-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[4-(pyridin-2-ylmethanesulfinyl)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[6-(4,4,5,5,5-pentafluoro-pentylthio)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[6-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[6-(pyridin-2-ylmethanesulfinyl)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(pyridin-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(furan-2-ylmethylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(thien-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(furan-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(furan-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(thien-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(thien-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(3,3,4,4,5,5,5-heptafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[2-(2-hydroxy-ethylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-fluoro-butylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-fluoro-butanesulfinyl)-pentyloxy]-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4,4,4-trifluoro-butylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4,4,4-trifluoro-butanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
5-(4-{5-[methyl-(4,4,5,5,5-pentafluoropentyl)-amino]-pentyloxy}-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-[4-(5-benzylthio-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-[4-(5-benzylsulfinyl-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-methyl-benzylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-methyl-benzylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-[4-(5-phenylthio-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-[4-(5-phenylsulfinyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-[4-(5-phenylsulfonyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-tert-butyl-phenylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-tert-butyl-phenylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
5-{4-[5-(4-tert-butyl-phenylsulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydroxy-7H-benzocyclohepten-2-ol
6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol.
In addition to these compounds of general formula I, if a nitrogen atom is contained in side chain Y, this invention also relates to their physiologically compatible addition salts with organic and inorganic acids, these compounds of general formula I including the pharmaceutical preparations that contain addition salts as well as their use for the production of pharmaceutical agents.
Inorganic and organic acids, as they are known to one skilled in the art for the formation of physiologically compatible salts, are suitable for the formation of acid addition salts. As addition salts with acids, especially hydrochlorides, hydrobromides, acetates, citrates, oxalates, tartrates and the methanesulfonates can be mentioned.
The compounds of general formula I represent compounds with strong antiestrogenic activity.
The compounds according to the invention are selective estrogens, whose action occurs in a tissue-selective manner. The estrogenic action occurs in particular on bones. No estrogenic action or only a slight estrogenic action occurs in the uterus and in the liver, however.
The compounds can also have antiestrogenic activity, which can be detected, for example, in an anti-uterus growth test or in tumor models. Compounds with such a profile have recently been designated as Selective Estrogen Receptor Modulators (SERMs) (Structure-Activity Relationships of Selective Estrogen Receptor Modulators: Modifications to the 2-Arylbenzothiophene Core of Raloxifene, T. A. Grese et al., J. Med. Chem. 1997, 40, 146-167).
The most prominent representative of this compound class is raloxifene, which is now allowed as a medication for the prevention and the treatment of postmenopausal osteoporosis.
Compounds with antiestrogenic properties, i.e., substances with inhibiting actions relative to estrogens, have already been described extensively. In this case, these are compounds both with a steroidal and with a non-steroidal skeleton.
The tamoxifen that became known for the first time from BE 637,389, (Z)-2-[4-(1,2-diphenyl-1-butenyl)-phenoxy]-N,N-dimethylethylamine, has been used for breast cancer therapy longer than antiestrogen.
Raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl]benzo[b]-thiophene, and its hydrochloride can be used for treatment and prophylaxis of osteoporosis (EP 0 584 952 B1).
The steroid derivative 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol (EP A 0 138 504, page 58, penultimate compound) that became known from EP A 0 138 504 B1 is currently under clinical development for hormone-dependent tumors (breast cancer).
Pharmaceutical compositions, which contain sex steroid inhibitors and which have a steroidal skeleton that has a 7xcex1-side chain in the case of the simultaneous presence of at least one additional substituent in 14-, 15- or 16-position, are the subject of EP-A 0 376 576. This patent application also relates to non-steroidal, antiestrogenic compounds, i.a., the compound EM 800. This compound was described originally as a pure antiestrogen; it has now been found, however, that this compound also has a clear partial estrogenic action.
The estrogen agonists and antagonists that became known from WO 96/21656 are, i.a., benzocyclopentane, hexane and heptane derivatives, which in the aromatic portion carry a hydroxy group, a nitrogen aromatic compound on carbon atom 5 or a phenyl radical that is provided with a side chain in 4-position and a phenyl radical that optionally has a side chain on carbon atom 6, i.a. Compounds with an unsaturation in the slightly condensed structural part are not disclosed there. Actually, merely benzocyclohexane derivatives are described.
Some compounds with a benzocycloheptene basic structure are found in various publications (Mol. Pharmacol. 1991, 39: 421-428; J. Med. Chem., 1986, 29, 2053-2059; J. Med. Chem., 1988, 31, 1316-1326). These compounds have in 4-position the phenyl radical that is bonded to carbon atom 5, a methoxy group, a 2-(dimethylamino)ethoxy group or a 2-(1-pyrrolidinyl)ethoxy group. It is not said of these compounds that they are selective estrogens.
Pharmacological Study of the Compounds According to the Invention
The influence of the compounds according to the invention on the uterus was studied in the uterus growth test (estrogenic action) and in the anti-uterus growth test (antiestrogenic action), both performed on infant rats.
Estrogenic/Antiestrogenic Action in Vivo Uterus Growth Test on Infant Rats (n=5 Animals/Group)
In infant animals, both uterus and vagina show a weight increase that is dependent on the estrogenic activity in their treatment with an estrogenically active substance. In the uterus, under estrogenic action, this results, moreover, in a proliferation and level increase of the luminal epithelium. Immature, normal rats (body weight 40-50 g) receive the substance s.c. over 3 days (d1-d3). On day 4 (d4), the animals are sacrificed with CO2. The uteri are prepared outside and weighed. A piece of the uterus, preferably a uterine horn, is set in formaldehyde for histological evaluation and embedded in paraffin. The stimulation of the organ weights (relative to mg/100 g of body weight) as well as the epithelial level are indicated in percentage stimulation in comparison to the reference compound 17xcex2-estradiol. (Substitution dose E2 0.3 xcexcg/animal).
The compounds according to the invention have no effect or an only slightly stimulating effect on the uterus.
Antiuterus Growth Test on Infant Rats (n=5 Animals/Group)
The uterus of infant estrogen-substituted rats can be used as a test model to detect a direct action of substances with antiestrogenic properties. The parameter of the estrogen action is the uterus growth that is induced by estradiol in infant rats, which is inhibited by the simultaneous administration of a substance with antiestrogenic action.
The test substances are treated s.c. on 3 successive days (d1-d3) in combination with a substitution dose of 0.3 xcexcg/animal/day of 17xcex2-estradiol. As a positive control, 17xcex2-estradiol is used alone; as a negative control, the vehicle group is used. On day 4 (d4), the animals are sacrificed, uteri and vaginae are prepared outside and weighed. The organ weights are calculated in mg/100 g of body weight, then the mean value and the standard deviation for each dosage is calculated. The inhibition of the uterus or vaginal growth that is induced by 17xcex2-estradiol is indicated as inhibition in %.
The compounds according to the invention for the most part show a clearly pronounced inhibition of the uterus growth that is induced by 17xcex2-estradiol.
Thus with respect to their action on the uterus, the compounds according to the invention are superior to the compounds of the prior art for the purposes of this invention to the extent that they have less or even no estrogenic action on this organ.
Bone Studies
Method
3-month-old female rats are ovariectomized and treated once daily with the test compound immediately after the operation for 28 days. The administration is carried out subcutaneously in peanut oil/ethanol. The animals are sacrificed on the day after the last administration, and tibia as well as uteri are removed. The uteri are weighed, set and worked up for histological studies. The determination of bone density is carried out ex vivo on prepared long bones using pQCT (quantitative computer tomography). The measurements are carried out at a distance of 4-6 mm from the ball of the joint of the proximal tibia.
The density of the trabecular bone in the measured area is reduced by the ovariectomy from about 400 mg of Ca2+/cm3 to about 300 mg of Ca2+/cm3. The degradation of bone density is prevented or inhibited by the treatment with a compound of general formula I according to this invention (dosages of 0.1-100 xcexcg/animal/day). The bone density was measured at the proximal tibia.
With respect to their bone-protective action, the compounds according to the invention have an action that is comparable to the compounds of the prior art in the case of simultaneously weakened or absent uterotrophic estrogenic action.
Thus for the purpose of a selective action on the bone with respect to a weakened action on the uterus, the compounds according to the invention are more greatly dissociated than the compounds of the prior art.
The invention also relates to pharmaceutical preparations, which contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof), and the use of these compounds for the production of pharmaceutical agents, especially for the indications below.
The compounds can be used both after oral and parenteral administration for the following indications:
Alleviation of the symptoms of male menopause and female menopause, i.e., for male and female hormone replacement therapy (HRT), specifically both for prevention and for treatment; for treatment of symptoms accompanying a dysmenorrhea; treatment of dysfunctional uterine bleeding; treatment of acne; prevention and treatment of cardiovascular diseases; treatment of hypercholesteremia and hyperlipemia; prevention and treatment of arteriosclerosis; for inhibition of the proliferation of arterial smooth muscle cells; for treatment of the respiratory distress syndrome in newborn children; treatment of primary pulmonary high blood pressure; for prevention and treatment of osteoporosis (Black, L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.; Williams, D. C.; Cullinan, G. J.; Bendele, R.; Kauffman, R. F.; Bensch, W. R.; Frolik, C. A.; Termine, J. D. and Bryant, H. U.: Raloxifene [LY 139481 HCl] Prevents Bone Loss and Reduces Serum Cholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats; J. Clin. Invest. 93: 63-69, 1994); for prevention of bone loss in postmenopausal women, in women who have had hysterectomies or in women who were treated with LHRH agonists or antagonists; inhibition of spermatic maturation; treatment of rheumatoid arthritis; for prevention of Alzheimer""s disease; treatment of endometriosis; treatment of myomas; treatment of myomas and endometriosis in combination with LHRH analogues; treatment of hormone-dependent tumors, e.g., breast cancer, treatment of prostatic diseases.
In addition, the compounds according to the invention are suitable based on their pharmacological profile both for male and for female contraception.
The compounds can also be used in combination with the natural vitamin D3 or with calcitriol analogues for bone degradation or as supporting therapies to therapies that cause bone mass loss (for example therapy with glucocorticoids, chemotherapy).
Finally, the compounds of general formula I can be used in connection with progesterone receptor antagonists or in connection with pure estrogens, specifically especially for use in hormone replacement therapy and for treatment of gynecological disorders and for female birth control.
A therapeutic product that contains an estrogen and a pure antiestrogen for simultaneous, sequential or separate use of the selective estrogen therapy of perimenopausal or postmenopausal conditions is already described in EP-A 0 346 014.
The amount of a compound of general formula I that is to be administered fluctuates within a wide range and can cover any effective amount. Based on the condition to be treated and the type of administration, the amount of administered compound can be 0.01-10 mg/kg of body weight, preferably 0.1-5 mg/kg of body weight, per day.
In humans, this corresponds to a dose of 0.8 to 800 mg, preferably 8 to 400 mg, daily.
A dosage unit contains, according to the invention, 0.4 to 400 mg of one or more compounds of general formula I.
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredient one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants and other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopxc3xa4die der technischen Chemie [Ullmans Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 ff. issued by Czetsch-Lindenwald, Hilfsstoffe fxc3xcr Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, pages 72 and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor K G, Aulendorf in Wxc3xcrttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue.
For oral administration, capsules, pills, tablets, coated tablets, etc. are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, oils are very frequently used with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifier. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated in such a way that a delayed release of active ingredient is made possible.
As inert materials, implants can contain, for example, biodegradable polymers or synthetic silicones such as, for example, silicone rubber.
In addition, the active ingredients can be added for percutaneous administration, for example, to a patch.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena(copyright)) that are loaded with active compounds of general formula I for local administration, various polymers are suitable, such as, for example, silicon polymers, ethylene vinyl acetate, polyethylene or polypropylene.
To achieve better bioavailability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with xcex1-, xcex2- or xcex3-cyclodextrin or derivatives of the latter (PCT/EP95/02656).
According to the invention, the compounds of general formula I can also be encapsulated with liposomes.
The compounds of general formula I according to the invention are produced as described in the examples. By an analogous procedure using reagents that are homologous to the reagents that are described in the examples, all compounds of general formula I can be obtained.
Etherification and/or esterification of free hydroxy groups is carried out according to the methods that are common to one skilled in the art.
The compounds of general formula I, in which A stands for a direct bond, can be obtained, for example, analogously to the processes that are described in WO 98/07740 and DE 1 98 06 357.1. To introduce side chain SK, first the 4-hydroxy group of the phenyl radical in 5-position of the starting product is converted into a trifluoromethylsulfonyloxy group and then palladium-catalyzed, and an alkylation on the phenyl radical is carried out to introduce terminally functionalized radical B (J. Org. Chem., 58; 8; 1993, pp. 2201-2208; Tetrahedron Lett. 28: 21; 1987, pp. 2387-2388). The further processing for the creation of complete side chain SK is then carried out as described in WO 98/07740 or DE 1 98 06 357.1.